It is known that certain mevalonate derivatives inhibit the biosynthesis of cholesterol, cf. F. M. Singer et al., Proc. Soc. Exper. Biol. Med., 102 270 (1959) and F. H. Hulcher, Arch. Biochem. Biophys., 146 422 (1971). Nevertheless the activity of the known compounds has not always been found satisfactory, i.e. to have practical application.
Recently, Endo et al. reported (U.S. Pat. Nos. 4,049,495; 4,137,322; and 3,983,140) the production of a fermentation product which was quite active in the inhibition of cholesterol biosynthesis. This natural product, now called compactin, was reported by Brown et al. (J. Chem. Soc. Perkin I, 1165 (1976)) to have a complex mevalonolactone structure. However, the low rate of production from fermentation broths appears to limit the supply of this natural product.
More recently, Willard et al. (Ser. No. 67,574, filed Aug. 17, 1979) described synthetic analogs of Endo's fermentation product whose biological activity closely approximated the natural product. As the structure-activity relationship within the Willard et al. compounds was developed, the desirable structures were seen to be derived especially from 2,4-dichloro-6-substituted benzaldehydes or 2,4-dimethyl-6-substituted benzaldehydes in which the 6-substituent was a substituted phenyl. Methods of preparation of the substituted biphenyl-2-carboxaldehydes were not readily available.
Stokker (copending application Ser. No. 140,275, filed Apr. 14, 1980) devised a six-step process which made the desired aldehydes in 30-35% yield. The number of reaction steps and the low overall yield limit the usefulness of that process. Murahashi et al. (J. Org. Chem., 43 4099 (1978) and Tetrahedron Letters 3749 (1974)) has described a method of preparing ortho- substituted benzaldehydes which comprises reacting a cyclic palladium complex of benzaldehyde aniline Schiff bases with a Grignard reagent in the presence of four molar equivalents of triphenylphosphine. When this reaction was tried with the substituted benzaldehydes and Grignard reagents having substituents needed for the Willard et al. inhibitors, an unusable mixture of various aldehydes was obtained.